This phase I/II trial studies the side effects and the best dose of veliparib when given together with radiation therapy and temozolomide and to see how well they work in treating younger patients newly diagnosed with diffuse pontine gliomas. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells either by killing the cells or by stopping them from dividing. Giving veliparib with radiation therapy and temozolomide may kill more tumor cells.

A Phase I/II Study of ABT-888, an Oral Poly(ADP-ribose) Polymerase Inhibitor, and Concurrent Radiation Therapy, Followed by ABT-888 and Temozolomide, in Children With Newly Diagnosed Diffuse Pontine Gliomas (DIPG)

Feasibility of intra-patient dose escalation of temozolomide during maintenance therapy with veliparib (Phase I and II) [ Time Frame: 28 days ] [ Designated as safety issue: No ]

Overall survival (Phase II) [ Time Frame: Time from initiation of therapy to the date of death from any cause or to the date patient was known to be alive for surviving patients, assessed to up to 3 years ] [ Designated as safety issue: No ]

Patients who have not failed (died) at the time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.

Secondary Outcome Measures:

PFS (Phase II) [ Time Frame: Time from initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second malignancy), assessed up to 3 years ] [ Designated as safety issue: No ]

Patients who start other anti-cancer therapy prior to disease progression will be censored in the Kaplan-Meier estimate of PFS as of the date the alternative therapy began. Patients who have not failed (died) at the time of analyses will be censored at their last date of contact in the Kaplan-Meier estimate of the PFS (overall survival) distribution.

Number of pseudo progression [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]

Pharmacokinetic parameters of veliparib [ Time Frame: At baseline, at 0.5, 1, 2 and 6-8 hours of day 1, and at day 4 ] [ Designated as safety issue: No ]

Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central compartment, elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance on dose-normalized parameters.

Other Outcome Measures:

Change in level PARP activity measured in PBMCs [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]

Cox models to explore associations between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ activity or gamma-H2AX levels and PFS and OS. Associations between these parameters and objective response may also be explored provided a large enough number of responses are observed. Otherwise correlations between PARP and NHEJ activity or gamma-H2AX levels with radiographic response and clinical outcome will be summarized descriptively.

Change in level NHEJ activity measured in PBMCs [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]

Cox models to explore associations between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ activity or gamma-H2AX levels and PFS and OS. Associations between these parameters and objective response may also be explored provided a large enough number of responses are observed. Otherwise correlations between PARP and NHEJ activity or gamma-H2AX levels with radiographic response and clinical outcome will be summarized descriptively.

Change in level gamma-H2AX measured in PBMCs [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]

Cox models to explore associations between the molecular parameters from correlative biology aims 1-2, namely PARP and NHEJ activity or gamma-H2AX levels and PFS and OS. Associations between these parameters and objective response may also be explored provided a large enough number of responses are observed. Otherwise correlations between PARP and NHEJ activity or gamma-H2AX levels with radiographic response and clinical outcome will be summarized descriptively.

Change in levels of urinary biomarkers [ Time Frame: Baseline to up to 3 years ] [ Designated as safety issue: No ]

Median levels for tumor patients will be compared to levels in healthy age- and gender-matched controls using the Mann-Whitney U-test. Multivariable logistic regression models coupled with receiver operating characteristic analyses will be used to select a combination of these biomarkers in an attempt to improve their collective performance as a classifier.

MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, are eligible without histologic confirmation; patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma, or fibrillary astrocytoma

Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible;

Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician

Patient must be able to swallow oral medications to be eligible for study enrollment

Karnofsky >= 50% for patients > 16 years of age or Lansky >= 50% for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

Patients must have not received any prior therapy other than surgery and/or steroids

Female patients of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test

Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study

Signed informed consent according to institutional guidelines must be obtained; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results

Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy

Patients with active seizures or a history of seizure are not eligible for study entry, with the exception of patients with documented febrile seizure

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01514201